Production of angiogenesis mediators and the structure of the vascular wall in the heart in ischemic cardiomyopathy

Background. In the pathogenesis of ischemic cardiomyopathy (ICMP), angiopoiesis remains unexplored.

The aim. To describe the vasculature of the heart and the imbalance of angiogenesis mediators in the coronary circulation in association with the number of endothelial progenitor cells (EPC) and desquamated endothelial cells (DEC) in the blood of patients with coronary heart disease (CHD), suffering and not suffering from ICMP.

Methods. Fifty-two patients with CHD (30  patients with ICMP, 22  patients without  ICMP), 15  healthy donors were examined. The content of EPC (CD14⁺CD34⁺VEGFR2⁺) in the blood from the cubital vein and DEC (CD45^–CD146⁺) in the blood from the coronary sinus and the cubital vein was determined by flow cytometry. The concentrations of VEGF-A (vascular endothelial growth factor A), PDGF (platelet-derived growth factor), and SDF-1 (stromal cell-derived factor 1) in blood plasma were recorded using immunofluorescence assay; the angiopoietin-2, MMP-9 (matrix metallopeptidase 9) were recorded using enzyme immunoassay. In myocardial biopsies the specific area of vessels and the expression of αSMA (smooth muscle alpha-actin) were determined by morphometric and immunohistochemical methods.

Results. In the peripheral blood of patients with CHD, regardless of the presence of ICMP, the DEC content exceeded the physiological level, and the VEGF-A, PDGF, angiopoietin-2, and MMP-9 corresponded to the norm. In CHD patients without cardiomyopathy, there was an excess of SDF-1 and EPC in the blood from the cubital vein, and in ICMP, their physiological significance was noted. In the coronary blood flow in patients with CHD without cardiomyopathy, an increase in the concentration of PDGF was found, which was not determined in patients with ICMP, who had an increased content of DEC, angiopoietin-2 and MMP-9. The specific area of the vessels in the patients of the two groups was comparable; the expression of αSMA in ICMP was 6.2 times lower than in patients with CHD without cardiomyopathy.

Conclusion. The development of ICMP is accompanied by impaired maturation of vessels in the myocardium, associated with the absence of a compensatory reaction of activation of cellular and humoral factors of angiogenesis.

1. Del Buono MG, Moroni F, Montone RA,Azzalini L, Sanna T, Abbate A. Ischemic cardiomyopathy and heart failure after acute myocardial infarction. Curr Cardiol Rep. 2022; 24(10): 1505-1515. doi: 10.1007/s11886-022-01766-6

2. Shipulin VM, Pryakhin AS, Andreev SL, Shipulin VV, Chumakova SP, Ryabova TR, et al. Modern clinical and fundamental aspects in the diagnosis and treatment of patients with ischemic cardiomyopathy (review). The Siberian Journal of Clinical and Experimental Medicine. 2021; 36(1): 20-29. (In Russ.). doi: 10.29001/2073-8552-2021-36-1-20-29

3. Gyöngyösi M, Winkler J, Ramos I, Do QT, Firat H, McDonald K, et al. Myocardial fibrosis: Biomedical research from bench to bedside. Eur J Heart Fail. 2017; 19(2): 177-191. doi: 10.1002/ejhf.696

4. Dang H, Ye Y, Zhao X, Zeng Y. Identification of candidate genes in ischemic cardiomyopathy by gene expression omnibus database. BMC Cardiovasc Disord. 2020; 20(1): 320. doi: 10.1186/s12872-020-01596-w

5. Poston RN. Atherosclerosis: Integration of its pathogenesis as a self-perpetuating propagating inflammation: A review. Cardiovasc Endocrinol Metab. 2019; 8(2): 51-61. doi: 10.1097/XCE.0000000000000172

6. Zhang J. Biomarkers of endothelial activation and dysfunction in cardiovascular diseases. Rev Cardiovasc Med. 2022; 23(2): 73. doi: 10.31083/j.rcm2302073

7. Melnikova YS, Makarova TP. Endothelial dysfunction as the key link of chronic diseases pathogenesis. Kazan Medical Journal. 2015; 96(4): 659-665. (In Russ.). doi: 10.17750/KMJ2015-659

8. Eligini S, Cosentino N, Fiorelli S, Fabbiocchi F, Niccoli G, Refaat H. Biological profile of monocyte-derived macrophages in coronary heart disease patients: implications for plaque morphology. Sci Rep. 2019; 9(1): 8680. doi: 10.1038/s41598-019-44847-3

9. Xu H, Jiang J, Chen W, Li W, Chen Z. Vascular macrophages in atherosclerosis. J Immunol Res. 2019: 4354786. doi: 10.1155/2019/4354786

10. Moroni F, Ammirati E, Norata GD, Magnoni M, Camici PG. The role of monocytes and macrophages in human atherosclerosis, plaque neoangiogenesis, and atherothrombosis. Mediators Inflamm. 2019; 2019: e7434376. doi: 10.1155/2019/7434376

11. Chopra H, Hung MK, Kwong DL, Zhang CF, Pow EHN. Insights into endothelial progenitor cells: Origin, classification, potentials, and prospects. Stem Cells Int. 2018; 2018: 9847015. doi: 10.1155/2018/9847015

12. Denisenko OA, Chumakova SP, Urazova OI. Endothelial progenitor cells: Origin and role of angiogenesis in cardiovascular diseases. The Siberian Journal of Clinical and Experimental Medicine. 2021; 36(2): 23-29. (In Russ.). doi: 10.29001/2073-8552-2021-36-2-23-29

13. Cao G, Xuan Х, Hu J, Zhang R, Jin H, Dong H. How vascular smooth muscle cell phenotype switching contributes to vascular disease. Cell Commun Signal. 2022; 20: 180. doi: 10.1186/s12964-022-00993-2

14. Felker GM, Shaw GM, O’Connor CM. A standardized definition of ischemic cardiomyopathy for use in clinical research. J Am Coll Cardiol. 2002; 39(2): 208-210. doi: 10.1016/s0735-1097(01)01738-7

15. Sarkisov DS, Perov YuL. Microscopy technique. Moscow: Meditsina; 1996. (In Russ.).

16. Avtandilov GG. Medical morphometry. Moscow: Meditsina; 1990. (In Russ.).

17. Zimna A, Kurpisz M. Hypoxia-inducible factor-1 in physiological and pathophysiological angiogenesis: Applications and therapies. Biomed Res Int. 2015; 2015: 549412. doi: 10.1155/2015/549412

18. Sun J, Shen H, Shao L, Teng X, Chen Y, Liu X, et al. HIF-1α overexpression in mesenchymal stem cell-derived exosomes mediates cardioprotection in myocardial infarction by enhanced angiogenesis. Stem Cell Res Ther. 2020; 11: 373. doi: 10.1186/s13287-020-01881-7

19. Wang X, Jiang H, Guo L, Wang S, Cheng W, Wan L, et al. SDF-1 secreted by mesenchymal stem cells promotes the migration of endothelial progenitor cells via CXCR4/PI3K/AKT pathway. JMol Histol. 2021; 52: 1155-1164. doi: 10.1007/s10735-021-10008-y

20. Apte RS, Chen DS, Ferrara N. VEGF in signaling and disease: Beyond discovery and development. Cell. 2019; 176(6): 1248-1264. doi: 10.1016/j.cell.2019.01.021

21. Laakkonen JP, Lähteenvuo J, Jauhiainen S, Heikura T, YläHerttuala S. Beyond endothelial cells: Vascular endothelial growth factors in heart, vascular anomalies and placenta. Vasc Pharmacol. 2019; 112: 91-101. doi: 10.1016/j.vph.2018.10.005

22. Zhou Y, Zhu X, Cui H, Shi J, Yuan G, Shi S, et al. The role of the VEGF family in coronary heart disease. Front Cardiovasc Med. 2021; 24(8): 738325. doi: 10.3389/fcvm.2021.738325

23. Bowler E, Oltean S. Alternative splicing in angiogenesis. Int J Mol Sci. 2019; 20(9): 2067. doi: 10.3390/ijms20092067

24. Chumakova S, Urazova O, Shipulin V, Vins M, Pryakhin A, Sukhodolo I, et al. Galectin 3 and non-classical monocytes of blood as myocardial remodeling factors at ischemic cardiomyopathy. IJC Heart Vasculat. 2021, 33: 100766. doi: 10.1016/j.ijcha.2021.100766

25. Sil S, Periyasamy P, Thangaraj A, Chivero ET, Buch S. PDGF/PDGFR axis in the neural systems. Mol Aspects Med. 2018; 62: 63-74. doi: 10.1016/j.mam.2018.01.006

26. Marushima А, Nieminen М, Kremenetskaia I, GianniBarrera R, Woitzik J, von Degenfeld G, et al. Balanced single-vector co-delivery of VEGF/PDGF-BB improves functional collateralization in chronic cerebral ischemia. J Cereb Blood Flow Metab. 2020; 40(2): 404-419. doi: 10.1177/0271678X18818298

27. Zhou J, Shao L, Yu J, Huang J, Fengcorresponding Q. PDGFBB promotes vascular smooth muscle cell migration by enhancing Pim-1 expression via inhibiting miR-214. Ann Transl Med. 2021; 9(23): 1728. doi: 10.21037/atm-21-5638

28. Xie Y, Liao J, Yu Y, Guo Q, Yang Y, Ge J, et al. Endothelial-tomesenchymal transition in human idiopathic dilated cardiomyopathy. Mol Med Rep. 2018; 17(1): 961-969. doi: 10.3892/mmr.2017.8013

29. Ha JM, Jin SY, Lee HS, Kum HJ, Vafaeinik F, Ha HK, et al. Akt1-dependent expression of angiopoietin 1 and 2 in vascular smooth muscle cells leads to vascular stabilization. Exp Mol Med. 2022; 54(8): 1133-1145. doi: 10.1038/s12276-022-00819-8

30. Zhang X, Chen CT, Bhargava M, Torzilli PA. A comparative study of fibronectin cleavage by MMP-1, -3, -13, and -14. Cartilage. 2012; 3(3): 267-277. doi: 10.1177/1947603511435273

31. Hamidi H, Ivaska J. Vascular morphogenesis: An integrin and fibronectin highway. Curr Biol. 2017; 27(4): R158-R161. doi: 10.1016/j.cub.2016.12.036